Cyclocreatine ((2-iminoimidazolidin-1-yl)acetic acid) is used in the treatment of creatine transporter defect. In this genetic disease, a mutation affects the creatine transporter thereby preventing creatine from crossing the blood-brain barrier (BBB), leading to a deficiency of this important amino acid in the brain. Creatine is a polar small molecule and requires active transport to cross the BBB. By contrast, cyclocreatine is more lipophilic owing to its two additional methylene groups and is able to cross the BBB by passive diffusion, thereby functioning as a creatine surrogate.
The synthesis of cyclocreatine was first reported in Rowley, G. L.; Greenleaf, A. L.; Kenyon, G. L. J. Am. Chem. Soc. 1971, 93, 5542-5551. The synthesis and characterization of cyclocreatine salts with pharmaceutically acceptable acids was later described in WO 2006/073923. The Rowley synthesis of cyclocreatine starts from the sodium salt of N-carboxymethyl-1,2-diaminoethane. This intermediate is maintained in solution and reacted with a methanolic solution of cyanogen bromide to afford the crude product, which is isolated by filtration from the reaction mixture. Final recrystallization is performed from water to afford the purified product.
The Rowley synthesis, however, is limited by poor overall yield. Further, the use of cyanogen bromide, a highly toxic and reactive compound, requires significant engineering controls for use on scale. More specifically, cyanogen bromide is a low-melting solid with a significant vapor pressure (mp=50-53° C., bp=61-62° C.) and is toxic by inhalation, dermal exposure, and oral ingestion. Indeed, plasma levels of 2.5 μg/mL cause convulsions and death in mice.
A need exists in the art, therefore, for a new synthesis of cyclocreatine and analogs thereof that is less toxic and provides for products in greater yield and at a lower commercial cost.